Automatic test parameters compensation of a real time fluid analysis sensing device

ABSTRACT

A method for automatic fluid flow compensation in disposable fluid analysis sensing devices is disclosed. The method is designed to keep the test conditions from sample to sample substantially unchanged. This is accomplished by using information about the preceding and/or current test measurements to automatically offset parameter variations of the disposable devices and the reading apparatus caused by manufacturing tolerances, wear of the mechanical parts, fluid viscosity differences and others. At each consecutive test measurement the method uses a compensation of the position of the actuating element to offset the difference between the previous test measurement and a factory pre-specified value. The method and system result, over the lifetime of the instrument, in a substantially unchanged flow of the analyzed fluid and reduction of the influence of a variety of external factors on the test measurements.

FIELD OF INVENTION

The present invention relates to a method and system for compensation oftest parameter variations. In particular, the invention relates to amethod and system for compensating the fluid flow deviations due to wearand other factors influencing the performance of a real time fluidanalysis test system.

BACKGROUND OF THE INVENTION

The testing of blood or other body fluids for medical evaluation anddiagnosis has traditionally been performed in large, well equippedcentralized laboratories. Such laboratories offer a wide range ofefficient and accurate testing procedures for a high number of fluidsamples. Centralized processing of fluid test samples has importantadvantages including the use of sophisticated, automated analyticaltechnology and highly trained personnel capable of calibrating andactively controlling operating parameters of this technology. However,the centralized type of testing has a number of disadvantages as well.An important one, for example, is that the test results are typicallynot immediately available to the physician who requested the test.Delays reaching several days are often caused by the fact that eachsample has to be collected, transported to the centralized laboratoryand then processed. The analysis results can only then be communicatedto the physicians, so that even in a hospital setting there may besignificant delays, jeopardizing on occasions the patient's health. Inaddition, test instruments designed for processing large numbers ofsamples, require specialized maintenance, especially for elements of thesystem in contact with the fluid, such as sensors and flow paths.Therefore, there is a recognized need for testing apparatuses whichwould permit the physician to obtain immediate results while examining apatient, whether in his office, in the hospital emergency room, or atthe patient's bedside elsewhere in a hospital.

A number of prior art testing systems have been designed to meet suchneed. Many devices are only capable of making simple test measurements.For example, well known are glucose meters, based on the use ofcalorimetric strips which require the tested fluid to be directlyapplied to a sensing region. Other test systems, such as the Biotrack PTanalyzer made by the Ciba Corning Diagnostics Corp. rely on passivecapillary draw within a cartridge to move the test fluid to the sensingregion. A similar approach is used in systems such as the Kyoto Daiichiglucose sensor, the U.S. Surgical Corporation's Statcrit hematocritsensor system and the Hemocue glucose and hematocrit cartridges made byMallinkrodt Sensor Systems, Inc. In a different approach, the TASinstrument made by Cardiovascular Diagnostics generates an oscillatingmagnetic field which causes magnetic particles to dissolve and mix afluid contained within the cartridge. In all these products, the testsystem is adapted for relatively simple measurements with no instrumentcontrol over the actions of fluids within the cartridges.

Other prior art fluid analysis systems can perform more complexmeasurements and have a correspondingly more complicated design. Severalsystems of this type (notably the Abbott Vision system and the EPOC testsystem developed by Abaxis) use centrifugal forces created by high-speedrotation of a cartridge containing the test sample to separate out itsmajor components, and an optical analysis instrument which relies onoptical transmission differences to make the measurement. This designapproach is, however, not suitable for bedside analysis due to the largesize of the instrument.

In order to avoid the problem of specialized maintenance of portions ofthe test equipment which are in direct contact with the test samples,several prior art sensing instruments utilize disposable testmeasurement cartridges. For example, the test system disclosed in U.S.Pat. Nos. 4,301,412 and 4,301,414 to Hill et al. employs a disposablesample card carrying a capillary tube and two electrodes. The samplecard is inserted into an instrument to read the electrical potentialgenerated at the electrodes. While simple conductivity measurements canbe made with this system, there is no provision for the full range oftests which are generally desirable. Similarly, the device disclosed inU.S. Pat. No. 4,756,884 to Hillman et al. only provides limited testingcapabilities with a transparent plastic capillary flow card whichpermits external optical detection of the presence of an analyte.

Other prior art devices of more general utility suffer the disadvantagethat excessive manual intervention is necessary in the testing process.For example, U.S. Pat. No. 4,654,127 to Baker et al., shows a single-usesensing device having a species-selective sensor in a test chamber. Theoperator must manually fill a sample chamber with the test sample, inputdata to a reading instrument, and respond to prompts from theinstrument. Then, the device is manually inserted into the readinginstrument. When prompted by the instrument, a further manual rotationof the reservoir releases the sample to the sensors under the force ofgravity. Although equipment of this type is capable of performing auseful range of tests, the high number of manual operations involved ininteracting with an instrument produces a correspondingly high number ofopportunities for an operator error in timing or technique, which mayand often does have a detrimental impact on the reliability of theperformed measurements.

Yet another solution is presented by the Biotrack 516 apparatus made byCiba Corning Diagnostics Corp. for agglutination assays. The system is aportable analyzer based on a discardable cartridge which houses twoglass vials filled with fluids. After the blood sample passes under theforce of gravity into a chamber, the instrument sequentially breaks thevials, releasing fluid to dilute and prepare the sample for themeasurement. While requiring relatively little experience from theoperator, the system presents no possibility to automatically adjusttest measurement parameters.

Thus, while in many cases presenting viable alternatives to thecentralized processing testing, prior art products also sharesubstantial shortcomings including a relatively narrow range of testcapabilities, lack of control over the test parameters which control iscritical for the consistency of the test results over time, and thefrequent necessity of employing highly trained laboratory technicians toperform the measurements and maintain the equipment in order to assuretheir accuracy and reliability and enhance the usefulness of theobtained results.

In order to overcome such limitations a test control system for realtime analysis must provide a portable, inexpensive way to make apparatuswith a fool-proof operation adaptable for a wide variety of tests. Foroptimal cost effectiveness, such a real time system would requireminimum skill to operate, while offering high testing speed, andconsistent and reliably accurate test results. Ideally, a successfuldevice would eliminate operator technique as a source of error byeliminating the need for manual intervention, while providing forautomatic correction and self-adjustment of the test parameters.

U.S. Pat. Nos. 5,096,669 (the "'669 patent") and 5,112,455 (the "'455patent"), assigned to the same assignee and hereby explicitlyincorporated by reference describe a system for testing blood which canbe used by a physician to obtain immediate results at the patients side.The system consists of a hand-held, battery operated instrument and unitcartridges each of which is used to measure a multiplicity of analyteson a single whole blood sample. An important advantage of this system isthe fact that the process of using it requires minimum humanintervention. This feature ensures that the result delivered to thephysician can be relied upon with little concern as to the level ofskill of the individual who has performed the test. The i-STAT systembased on the disclosure of the '669 patent also eliminates the need forspecial maintenance of the sensors and the flow paths since these testcomponents are parts of a disposable cartridge replaced after eachmeasurement by a new one. Thus, the i-STAT product combines some of thebest elements of centralized laboratory instrumentation and hand-heldcartridge based systems.

Specifically, as described in the '669 patent, the instrument utilizes adisposable sensing device in which during the test two fluids areconsecutively moved over an array of sensors to determine theconcentration of substances in the test sample. The first fluid is usedfor calibration of the sensors and prior to use is housed in a sealedpouch on the cartridge. The second fluid is the actual test fluidsample, typically a blood sample.

In use, after the calibration of the sensor elements, the actualmeasurement is initiated by depressing an air bladder in the cartridgewhich forces air to move all fluids within the cartridge along the fluidpaths. In the process, the calibration fluid is first forced out of thesensor area. Next, the air bubble separating it from the test samplepasses over the sensors, and finally the blood sample is pushed over thesensors for a predetermined period of time to conduct the actualmeasurements.

The i-STAT system requires minimum physical intervention on the part ofthe operator and is very fast (test results from a variety ofmeasurements are typically obtainable within about 2 minutes). Inaddition, the disposable i-STAT system cartridge is provided with a pairof electrodes that comprise a conductivity sensor which measures theelectrical resistance of the fluids at each stage of the measurementprocess. This allows the instrument to monitor the test and, bycomparing measurement data to factory preset thresholds, determinewhether test parameters are deviating from the standard limits. (Forinstance this control can determine whether the operator has collectedsufficient blood sample to conduct a proper test).

Despite the apparent advantages of the i-STAT system it will berecognized by those skilled in the art that the mechanical elements ofits fluid flow control may wear over the lifetime of the instrument, orbecome misadjusted for various reasons, such as improper handling of thereader. Such variations can affect the amount of sample fluid which isdelivered to the sensors. These variations can in turn lead tovariations in the amount of "carryover" of calibrant into the sample(incomplete clearance of calibrant from the sensors by the sample). Asthe software instructions in the instrument include calibration factorsdesigned to determine concentrations of elements in the test samplebased upon a fixed nominal amount of carryover, these variations canultimately lead to an increased variation in the concentrations ofelements in the test sample reported by the instrument.

In order to keep the complexity of the system at a minimum and make itcost effective, the i-STAT device provides no means for the operator toadjust the mechanical system. Therefore, unless the instrument has theability to adjust itself, it would have to be returned back to thefactory if and when its fluid control system moves out of thespecification boundaries. Although optical and mechanical sensingdevices which would control the mechanical elements of the portablei-STAT system could be used these are not the best type of solutions dueto the complexity and cost of the required precision, compact design.

Thus, it is perceived that notwithstanding the advantages of thissystem, a software based method is required to automatically compensatefor various deviations which may occur during the life time of theinstrument as a result of mechanical wear, and other potential sourcesof measurement error. Such compensation may be used to relax therequirements on the precision mechanical parts of the instrument,increase the accuracy and reliability of the measurements and prolongthe useful life of the instrument.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a meansfor automatic correction of the operation of a fluid control system forreal time fluid sensing systems employing disposable cartridges.

It is another object of the present invention to provide an automaticcompensation method and a system capable of maintaining consistentperformance over the life time of a fluid sensing instrument underconditions of mechanical wear or misalignment of the mechanicalcomponents within the instrument.

It is yet another object of the present invention to provide a softwarebased method for the automatic compensation of the parametermisadjustments and a system to implement such method.

In accordance with the present invention the automatic compensationmethod and system are based on the characteristic signal seen at theoutput of a fluid conductivity sensor which is mounted on eachdisposable cartridge. The sensor output signal is proportional to theelectrical resistance measured between a pair of conductivity electrodesand can be used to determine the time when a particular fluid ispositioned between those electrodes. Specifically, the resistance of thecalibration solution typically has a relatively low, constant value. Asthe calibrating fluid is being displaced by the air bubble separating itfrom the test sample, the resistance measured between the electrodesrises sharply, due to the dielectric properties of the air. Finally, inthe last segment of the test process, the measured resistance drops backdown to a level determined by the electrochemical properties of theblood sample.

The sharp differential between the electrical resistance properties ofthe two fluids and the air enables the control system of the presentinvention to accurately determine the time relationships between themotions of the moving parts of the mechanical system and the flow offluids over the sensors. Thus, the time position relative to thebeginning of the test when the electrical resistance measurement reachesa first specified value (referred next as the rise time), and fallsbelow a second value (referred next as the fall time) can be used as anindication of the performance of the mechanized fluid control systemagainst predetermined specifications.

In accordance with the present invention there are two approaches tokeeping the test parameters substantially unchanged over a large set oftest measurements.

In one preferred embodiment of the present invention the automaticcompensation method is based entirely on measurements from the previouscartridges. In this method, the total fluid displacement time measuredfrom the beginning of the fluid displacement is kept constant.Similarly, the speed of the actuating element is constant in allmeasurements and the compensation is accomplished by changing theinitial position of the actuating element prior to the beginning of thefluid displacement. In operation, after each successful sensing, thesystem compares the rise time of the measured resistance curve to apreset factory threshold and marks the difference as being positive ornegative. This difference is stored and used in the followingmeasurement to correct the physical position of the actuating element.For example, if the rise time of the resistance curve is shorter thanthe factory preset value, the compensation method automatically adjuststhe initial position of the actuating element to start the actual motionof the fluid somewhat later during the next fluid displacementoperation.

Alternatively, if the measured rise time is longer than the presetfactory value, the method compensates by adjusting the initial positionof the actuating element so that for the next test cartridge the actualmotion of the fluid will start earlier during the next fluiddisplacement operation. (Physically, the corrections correspond topositioning the actuating element of the reader higher or lower withrespect to an air bladder in the cartridge described in the '669 patent,the depressing of which is used to initiate the fluid displacementduring test measurements). The unit correction amplitude after each testis identical, its direction being determined by the sign of thedifference between the resistance rise time during the previousmeasurement and the factory specified mean rise time value. The totalcorrection amplitude which is added to the factory preset value,however, is modified each time by adding or subtracting one unit to theprevious value. This mode of compensation ensures that it is targeted torespond to the relatively slow changes in the physical properties of thesystem associated with wear of mechanical components, without addingextra variability by responding to the relatively large sensing deviceto device variations in the fluid arrival times.

The first embodiment is preferred because it both maintains a constantlength of time for the fluid displacement operation and thereforeproviding the maximum precision to the signal processing algorithmsdescribed in the '455 patent and maintains a constant speed of fluiddisplacement to maintain maximum precision in the degree of carryover.

In a second and third embodiments of the present invention the volume ofthe test fluid samples delivered to the sensors is kept constant over aset of measurements by using not only data from previous measurementsbut concurrent sensor output information from the sensing device aswell. In accordance with these embodiments, both the speed of theactuation element and the fluid displacement time for test samplesensing may be varied during a test measurement. The goal in each caseis to ensure a constant volume of the test fluid sample passing over thesensors.

In accordance with the second embodiment of the present invention, thetarget time for a standard test fluid sample to pass over the sensors isused. For a constant speed of the actuation element this time isproportional to the sample volume moved over the sensor elements, sothat by keeping the fluid displacement time constant, the compensationmethod of the present invention effectively maintains a constant testsample volume. To this end, the instrument continuously monitors theoutput of the conductivity sensors. After the measured resistancereaches the second predetermined threshold (at the fall time of theresistance curve), indicating the time when the test sample is over thesensor elements, the actuation element is pressed for the target testtime. In this embodiment, the motion speed of the actuation element iskept constant.

In a third embodiment of the present invention, a target volume of thetest sample delivered to the sensors is maintained for each test bymodifying the speed of the actuating element, keeping the fluiddisplacement time constant.

The preferred embodiments of the present invention only require theimplementation of software based automatic compensation methods, whichby reducing variations of fluid displacement parameters effectivelyincrease the consistency and reliability of the output measurements madeby each sensor of the sensing device of the fluid sensing system.

BRIEF DESCRIPTION OP THE DRAWINGS

These and other objectives, features and advantages of the presentinvention are described in following detailed description of thepreferred embodiments and are illustrated in the accompanying figures inwhich:

FIG. 1 is an isometric view of a reader instrument and a disposablecartridge used in the fluid analysis sensing device of the presentinvention.

FIG. 2 is an isometric view of the disposable cartridge with its topportion removed.

FIG. 3A shows in a diagrammatic form the fluid paths and the sensorelements shown in FIG. 2.

FIG. 3B is an exploded view of a portion of the diagram in FIG. 3Aillustrating the conductivity sensors used in the compensation method.

FIG. 4 is a cross-sectional view of the reader instrument with thedisposable sensing cartridge partially inserted.

FIGS. 5 A, 5B and 5C show the position of the fluids at three differentpoints during the fluid displacement.

FIG. 5A shows the sample fluids at the beginning of the fluiddisplacement.

FIG. 5B shows the position of the fluid at a later point in time whenthe air segment is over the conductivity sensors.

FIG. 5C shows the position of the fluid at the end of the test when thesample fluid has been displaced over the sensor array.

FIG. 6 illustrates a typical resistance signal obtained from theconductivity sensor during the test measurement.

FIG. 7A, 7B and 7C illustrate possible variations of the resistancesignal due to mechanical wear and other factors influencing the testmeasurements.

FIG. 8 is a block diagram of a preferred embodiment of the automaticcompensation method of the present invention.

FIGS. 9A and 9B are block diagrams of a second and third preferredembodiments of the automatic compensation method of the presentinvention.

FIG. 10 is an illustration of effectiveness of the compensation methodat moving the average air segment rise time to a target value.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring first to FIG. 1, the test system 300 of the present inventioncomprises a self-contained disposable sensing device 10 and a reader150. To conduct the measurement, the test fluid sample to be sensed isfirst drawn into a chamber within the sensing device 10 which is theninserted into the reader 150 through slotted opening 360. Measurementresults providing indication of the desired fluid sample concentrationsare output to display 366 or other output devices, such as a printer.Following the test measurement, disposable sensing device 10 isautomatically ejected and the reader instrument is prepared to receivethe next sensing device.

Referring now to FIG. 2, sensing device 10 contains an array of sensorelements 70 and several cavities 18, 20, 22 and conduits 220, 224, 228,and 234 which enable the test fluid sample collection, provide activereagents, calibrate the sensors and enable the measurement bytransporting fluids to and from the sensor elements 70.

As shown in FIGS. 2 and 4 in the center of the device 10 is locatedfirst cavity 18 which has a pin 40 at its bottom, a hinged disk 102 atthe top and a first conduit 220 which leads from cavity 18. A sealedpouch 60 containing fluid adapted to calibrate the sensor elements 70resides in the cavity 18. A second conduit 224 has an orifice at one endfor the receipt of a test fluid sample, while the other end terminatesat a capillary break 222. A third conduit 228 leads from the capillarybreak 222 past the sensor elements 70 to a second cavity 20 which servesas a sink. The first conduit enters the third conduit between thecapillary break and the sensor array. A third cavity 22 serves as an airbladder 229. When the air bladder 229 is depressed, air is forced down afourth conduit 234 into the second conduit 224 displacing in the processthe fluids within the sensing device.

With reference to FIGS. 2 and 3A, the array of sensing elements 70 isdesigned to measure the specific chemical species in the fluid samplebeing tested. Preferably, each of the sensing elements comprises anarray of conventional electrical contacts 72 and array of selectchemical sensors 74 and circuitry for connecting individual sensors toindividual contacts. The electrochemical sensors 74 are exposed to andreact with the fluid sample to be measured generating electrical signalsindicative of the measurements being performed. The electrical signalsare output on the electrical contacts 72 which connect to an electricalconnector of the reader 150 for the transmission of electrical potentialvalues. A more specific description of the sensor array 70 is given inthe incorporated '669 patent.

FIG. 3A illustrates in a diagrammatic view the disposable sensingelement of FIG. 2 in which like elements are denoted with like numbers.(The diagram includes a sealing cap portion not shown in FIGS. 1 and 2.)Particularly important for the present invention is sensor 75 whichcomprises a pair of conductivity electrodes 76 and 78 and is shown in anexploded view in FIG. 3B. Electrodes 76 and 78 are adapted to measurethe electrical resistance of the substance between them, and communicateits value to the reader instrument.

In operation, when an orifice at one end of the conduit 224 is placed incontact with the test sample the fluid is first drawn by capillaryaction into the second conduit 224. After the test fluid sample fillsthe second conduit 224, the operator seals the orifice so that air frombladder 229 may force the fluid sample out of conduit 224.

In reference to FIG. 4, a cross section of the reader instrument 150 andthe disposable device 10 is illustrated in a partially inserted form.When device 10 is fully inserted, electrochemical sensors 70 andconductivity sensor 75 come in contact with the electrical contacts 432of the reader instrument indicating that the disposable sensing deviceis in position to start the measurement. At this time, pouch 60 ispierced causing the calibrant fluid to flow out of the pouch 60 throughthe first conduit 220 into the third conduit 228 and across theelectrochemical sensing elements 70, where measurements are taken withina pre-specified time period (typically about 60 sec) to calibrate thesensing array.

In reference to FIGS. 2, 3, and 4, once the calibration is complete, amechanical motor actuates the rotor 445 which moves in the directiontoward the sensing device 10. An actuating element 100 is caused topress down at the air bladder 229 formed by cavity 22 and forces the airdown the fourth conduit 234 into the second conduit 224 which in turnexpels the test fluid sample from the storage conduit 224. The airforces the test fluid sample across the capillary break 222 and into thethird conduit 228. The fluid sample is passed over the electrochemicalsensing arrays 70 and forces the calibrant fluid in the conduit 228 tooverflow into the waste sink defined by cavity 20. At this time,measurements are taken of the test sample which is in contact with theelectrochemical sensors 70. The resulting electrical potentials,indicative of the concentration of the chemical species, are output onthe electrical contact 72. These signals are transmitted throughelectrical connectors to the reader instrument which then performscalculations in accordance with a signal processing algorithm stored ina memory to determine the concentration of the measured species. Thisinformation is finally output to the display device or printer for useby the physician to perform medical analysis or diagnosis. Specifics ofthe operation of the device are disclosed in detail in U.S. Pat. No.5,096,669 which is incorporated by reference.

FIGS. 5A, 5B, and 5C illustrate consecutive periods of the describedfluid displacement cycle, where in FIG. 5A the fluid displacement hasjust begun (at time t0, immediately following the calibration of thesensor elements). FIG. 5B illustrates the second stage, when thecalibrant fluid is being forced into the sink, and the air bubbleseparating it from the test fluid sample is positioned over theconductivity sensor. Finally, FIG. 5C illustrates the test fluid samplepassing over electrodes 76 and 78.

It is important to note that the relative motion of the actuatingelement 100 of the sensing instrument is proportional to the number ofrevolutions made by a motor which drives the mechanically moving partsinside the reader 150. The number of revolutions can in turn bedetermined by monitoring the electromotive voltage generated by therotor as it turns, this signal being proportional to the rotationalspeed. The number of turns of the rotor required to achieve certainvertical position of the actuating member 100 for a specific instrumentcan be programmed into a non-volatile memory chip in the factory.Specific mathematical relationships between the involved quantities areillustrated in Appendix A.

FIG. 6 illustrates a typical signal observed at the output of theconductivity sensor 75 in the course of the fluid displacement. Theinitial time t0 indicates the resistance measurement at the beginning ofthe fluid displacement, immediately following the calibration of thesensor arrays 70. In a preferred embodiment of the present invention thefinal time Te has a factory preset value which is determined in acompromise between the measurement. speed and the accuracy requirements,as discussed in U.S. Pat. No. 5,112,455 which is incorporated byreference.

Three well defined time segments are distinguishable in FIG. 6. Thefirst segment, designated A, corresponds to the time period when thecalibration fluid is being pushed out of the sensor area but is stilldetermined by the resistance measured across electrodes 76 and 78 ofsensor 75. This resistance has a typically low, constant value for aquiescent calibrant fluid. In the following time segment B, the airbubble separating the calibrant fluid and the test fluid sample isforced to pass over the sensors, drying their active areas. The airbetween the electrodes 76, 78 causes the measured resistance to increasesignificantly. (See time segment B in FIG. 6.) In the final timesegment, denoted as C, the test fluid sample is forced by the motion ofthe actuating element to flow over the electrodes 76, 78. The typicaltest fluid samples are whole blood, which due to the concentration ofelectrolytes and non-conductive blood cells will have a resistancesomewhat larger than that of the calibrant fluid but still much lowerthan the high resistance of the air bubble. As the test fluid sampleflows over both sensors, flushing out any remaining calibrant fluid, themeasured resistance settles to a constant value which corresponds to theelectrochemical properties of the tested fluid sample. As is well knownin the art, the individual time segments of the measurement may beseparated by providing a threshold value(s), the crossing of whichdetermines the boundaries between adjacent segments. (Thus, the time atwhich the measured resistance crosses a first resistance threshold TH1defines the rise time t1 of the fluid displacement. Similarly, the timewhen the resistance drops below a second threshold value TH2 defines thefall time t2 of the fluid displacement).

The well defined time segments illustrated in FIG. 6 indicate theconnection between the displacement of fluids during the test and theresistance signal from the conductivity sensors. This relationship isthe basis for the automatic compensation method of the presentinvention.

FIGS. 7A, 7B, and 7C illustrate in a diagram form several possibleresistance curves in which the time segments A, B and C deviate from thenormal ones, due to mechanical wear, variations in the fill of fluids inthe sensing device, variations in cartridge to cartridge parameters, theviscosity of the sample, and other factors. As indicated, the change inthese figures, compared to the normal resistance curve defined in FIG.6, is shown as an increase or decrease in the rise time t1 and a shiftof the fall time t2 of the resistance curve, correspondingly. It isclear that time segment C which corresponds to the time during which thetest fluid sample is being brought across the conductivity sensorvaries. As the fluid tested by the other sensors is a mixture of thecalibrant and test sample fluids, due to a small amount of "carryover,"the variation in the amount of sample brought to the sensors leads to acomponent of variation of the measurements made by all the sensors inthe sensing device 10.

The deviations from the normal resistance curve, illustrated in FIG. 7indicate imprecisions in the amount of test sample passing over thesensors, the volume of the separating air segment and thus the amount ofcalibrant fluid which is carried over into the sample which is measuredby the sensors. Most of these variations are random from cartridge tocartridge and are caused by variations in the physical dimensions andcharacteristics of the different cartridges, the amount of test samplefluid, and the sample fluid viscosity. Additionally, there is acomponent of these variations that slowly increases over the life of theinstrument as the mechanical parts wear. This wear typically causes ashift in the initial position of the actuating element 100, which shiftincreases with the number of samples being tested.

The goal of the automatic compensation method of the present inventionis to counteract the factors which may contribute to the deviations ofthe test conditions from sample to sample. In accordance with apreferred embodiment of the invention, this is accomplished bydelivering a constant volume of test sample to the sensors at a constantspeed. This volume is determined by both the initial position of theactuating element of the reader 150 at the end of the calibrationperiod, and the length of the fluid displacement period. By monitoringthe electrical resistance response curve from the fluid displacement, itis possible to evaluate the performance of the mechanical fluid controlsystem after each test and compensate for minor variations from thefactory preset standard (target) values.

FIG. 8 is a block diagram of the method for automatic compensation inaccordance with a preferred embodiment of the present invention. At step1 actuating element 100 is positioned just above the air bladder 229 atthe end of the calibration period and the actual fluid displacement isready to start (t=t0). Calibrant fluid is still covering the electrodes76, 78 of sensor 75 and the measured resistance between them is low.

At step 2, the fluid displacement is initiated as actuating element 100is moved downward for a preset period of time, typically 3.5 seconds.The motion of element 100 causes air in air bladder 229 to displace allfluids within the fluid paths of the sensing device 10, as describedabove. At the same time, measurements of the resistance curve fromconductivity sensor 75 can be stored in a digitized form into a RAMmemory within the reader.

At step 3, the resistance rise and fall times t1 and t2, as defined inFIG. 6, are computed by comparing factory preset values stored in anon-volatile memory within the reader 150 to the resistance measurementfrom sensor 75.

In the next step, step 4 in FIG. 8, the computed rise time t1 iscompared to factory preset limits. Should the measured value exceedthose limits, an error message is displayed and the test isdiscontinued. This computation step is designed to uncover grossdeviations from the normal test parameters, such as a defective sensingdevice, lack or insufficient test fluid and others. By discarding suchdeviating samples, the method of the present invention avoids the use ofabnormal test characteristics in the compensation feedback loop. Thelimits may be determined statistically after examining a number of testsamples known to be good.

If the processing measurements are within limits, in the following step5 the test measurement proceeds to the end of the predetermined timeperiod T. If the rise/fall times t1/t2 had not been previously stored atstep 2, they are now stored in a RAM memory of the sensing instrument.

In step 6 of the method, the recorded rise time t1 of the resistancemeasurement is compared to a factory pre-specified threshold value(typically for blood tests this threshold is set at 0.85 seconds) whichcorresponds to the average expected resistance rise time. The sign ofthe computed difference at step 6 determines the direction of the motioncompensation in step 7 of the method. For example, if the rise time t1is shorter than the factory preset value, the compensation methodautomatically adjusts the initial position of the actuating element 100to start the actual fluid motion somewhat later during the next fluiddisplacement operation. If the measured rise time is longer than thepreset factory value, the method compensates by adjusting the initialposition of the actuating element so that for the next test cartridgethe fluid motion will start earlier. Alternatively, it may be theresistance fall time t2 which is compared to a factory pre-set targetvalue and used to determine the corrections in the position of theactuating element.

In accordance with the present invention, the correction value is storedas bits in a RAM memory within the reader 150. To reduce the sensitivityof the method to normal sensing device-to-device deviations around themean test conditions, which deviations may still fall between the limitsat step 4, after each test measurement the amplitude of the correctionto the actuation element motion is preferably kept constant. However,other correction algorithms within the spirit of the inventive conceptmay also be employed if required. The initial position of the actuatingelement at the start of the next fluid displacement is determined by twofactors: a factory preset value which is typically stored in anon-volatile memory of the reader; and a compensation value, whichdepends on the sign of the rise time comparisons for the previous testsamples and is accumulated in a RAM or an EEPROM memory of the reader150. Thus, if the parameters of the test measurements are consistentover a number of samples, the compensation value will be close to zero,so that the position correction of the actuating element from test totest will alternate between positive and negative. Alternatively, if therise time for a group of sensing devices is consistently larger orsmaller than the factory preset value, the corresponding correctionaccumulates, causing with each test the position of the actuatingelement to compensate for the changes until the instrument adaptivelybrings the test conditions to the standard.

Using conversion tables such as those shown in Appendix A, at step 8 ofthe method the stored corrections are translated into a physical motionof the actuating element (the correction is in fact stored as the numberof revolutions of the actuating motor). This motion determines theposition of the actuating element at the beginning of the next fluiddisplacement. Once this motion is determined, the compensation algorithmexits (step 9), leaving the device ready for the next test sample.

It should be noticed, that in order to minimize the memory accesses tonon-volatile memories which may have a limited number of read/writecycles, the compensation algorithm of the present invention may beadjusted to make a correction of the actuating element's motion everyM-th step, instead of using a correction after each measurement (Mtypically ranging from 2 to 100).

FIGS. 9A and 9B are block diagrams of a second and third embodiment ofthe present invention. These method embodiments are based on the factthat the speed of the actuating element and the time for completing themeasurement of the test sample may be accurately controlled byappropriately programming the motion of the actuating element.

In accordance with the second embodiment of the present invention, atarget time for a standard test fluid sample to pass over the sensors isused. (time segment C in FIG. 6). For a constant speed of the actuationelement this time is proportional to the sample volume moved over thesensor elements, so that by keeping the time during which the samplefluid is passing over the sensors constant, the compensation method ofthe present invention effectively maintains a constant test samplevolume.

Steps 1' and 2' of the method are similar to those in FIG. 8 but theinstrument continuously monitors the output of the conductivity sensors.After the measured resistance reaches the second predetermined thresholdTH2 (at the falling time of the resistance curve), at step 3' of themethod, the computed resistance rise/fall times are compared at step 4'to threshold limits causing the algorithm to exit, should abnormaldeviations be detected. At step 5', the actuation element 100 iscontinuously pressed for the predetermined average test time at step 6',if prior to the test completion there is indication of the end positionof the actuating element, the compensation algorithm exits with an errormessage. Otherwise, the test ends at step 7' indicating a normal testsample measurement. In this embodiment, the motion speed of theactuation element is kept constant for each test measurement.

In a third preferred embodiment of the present invention, a targetvolume of the test sample is passed over the sensors for each testmeasurement by keeping the fluid actuation time constant but modifyingthe speed of the actuating element. FIG. 9B shows a detail of thecompensation method in accordance with this embodiment, where likealgorithm steps are denoted with like numbers. The method steps 1"-4"are similar to those in FIG. 9A. At step 5", after the resistance falltime t2 is determined, the algorithm computes the time for a standardtest fluid sample to pass over the sensors (segment C in FIG. 6) for theparticular test measurement by subtracting the fall time from thepre-determined overall test time. In step 6" the computed test fluidsample time is used to calculate the speed of the actuating elementwhich is required in order to displace the target sample fluid volume.The speed adjustment is done in real time, so that at step 7" thealgorithm exits at the end of the test measurement.

In all embodiments of the present invention, the automatic compensationmethods are implemented by storing into the memory of the readerinstrument the corresponding algorithm steps and executing the routinesduring or after the actual test measurement. One or more algorithmswhich correspond to the above described embodiments may be stored andused at different times according to needs. The proposed compensationmethods do not require hardware modifications of the device disclosed inthe '669 patent, however, they contribute to reducing variations of testmeasurement parameters. The software based automatic compensationeffectively increases the consistency and reliability of the outputmeasurements of the i-STAT fluid sensing system.

FIG. 10 is an illustration of the typical sensing device to devicevariations and the results of the compensation method in accordance withthe first preferred embodiment of the present invention. Each linerepresents a series of rise time measured by individual instruments. Thecompensation method of the present invention is seen to move the averagerise time toward the target value of 0.85 seconds. The initial deviationfrom the target value may be due to mechanical wear or misadjustmentcaused by mishandling or other factors. While the automatic compensationmethod moves the average time toward the target value, it does notremove the inherent sensing device to device variability. This inherentvariability contributes one component to the variability of themeasurements made by the sensors. The compensation method of thisinvention reduces the contribution of other error components whichgradually affect the performance of the sensing instrument as it isbeing used.

While the present invention is particularly advantageous in the medicalenvironment and has been described in this context, it will beappreciated that it can be practiced in any situation where it isdesired to perform chemical analyses of a large number of test fluidsamples and is required to keep the test parameters relativelyunchanged. In addition, it is to be expressly understood that theclaimed invention is not to be limited to the description of thepreferred embodiments but encompasses other modifications andalterations within the spirit of the inventive concept which scope isdefined by the following claims.

                  APPENDIX A                                                      ______________________________________                                        Physical Constants in the Sensor Instrument                                   ______________________________________                                        1.     Relating Change in Actuating Element Position to                              Change in Air Segment Time.                                            2.     Relating Change in Actuating Element Motion to                         Back-EMF Bits                                                                 J = Y/R      mils/rotation!                                                   G = r/R      dimentionless!                                                   k = V/W      mVolts/1000's rpm!                                               E             mV*mS/bit!                                                      (E signifies that 1 bit corresponds to a unit back-EMF for                    a               unit period of time)                                          where the quantities above are defines as                                     follows:                                                                      Actuating element Motion                                                                           Y       mils!                                            Rotations of Leadscrew                                                                             R       rotations!                                       Rotations of Motor   r       rotations!                                       Rotation Rate of Motor                                                                             W       rotations                                        per msec!                                                                     Back-EMF Voltage     V                                                         millivolts!                                                                  Integrated Back-EMF  B       bits!                                            Time                 t       msec!                                            Dimensional Constants:                                                        1000 rotations per minute = (1/60) rotations per                              millisecond                                                                           so to express k in consistent dimensions use                                    60*k mV/rotations per msec                                          Using the above definitions, the ratio B/Y can be                             derived as:                                                                              B/Y = (60*k*G)/(J*E)                                               which is the expression used to control the                                   motion of the actuating element.                                              ______________________________________                                    

What is claimed is:
 1. An automatic compensation method for maintaining close to a target value a mean fluid displacement of test samples in a succession of test measurements of a fluid sensing instrument which includes an actuation mechanism for the displacement of at least one fluid along a predetermined fluid path and at least one sensor, the method comprising the steps of:(a) recording the time of arrival of each fluid at the sensor by measuring an output characteristic of the sensor; (b) for each successive test measurement determining the variation of the recorded arrival time from a predetermined value; and (c) compensating, in response to the determined variation, the motion of the fluid actuation mechanism in successive test measurements to keep the mean fluid displacement close to the target value.
 2. The method of claim 1 wherein the fluid path and the sensor are positioned in a disposable cartridge device replaced after each test measurement.
 3. The method of claim 1 wherein measurements of the output characteristics of the sensor in step (a) are stored in a memory during each test measurement and are compared at step (b) of the method to a value determined by a factory preset value corresponding to an average expected fluid arrival time.
 4. The method of claim 1 wherein step (b) further comprises the step of comparing the determined variation to preset maximum deviation limits and discontinuing the test measurement if the determined variation is larger than the preset limits.
 5. The method of claim 4 wherein the motion compensation of the actuation mechanism at step (c) is computed for each test sample from a factory preset value corresponding to an average expected fluid arrival time for test samples and from a value which is determined by the cumulative correction of variations in the previous test measurements.
 6. The method of claim 4 wherein a unit compensation of the motion of the fluid actuation mechanism at step (c) in each test measurement has a constant value which is independent of the value of the determined variations which are within the maximum deviation limits.
 7. The method of claim 1 wherein a unit compensation of the motion of the fluid actuation mechanism at step (c) in each test measurement is done in response to the sign of the determined variation.
 8. The method of claim 1 wherein the sensor measures the electrical conductivity of the fluids passing along the fluid path.
 9. The method of claim 8 wherein fluid samples in one test measurement having similar electrical conductivities are physically separated as to cause large deviations in the measured electrical conductivity signal at the output of the sensor.
 10. The method of claim 1 wherein in step (c) the compensation is different from a zero value only for every M-th measurement, where the value of M is selected between 2 and
 100. 11. The method of claim 2 wherein the compensation of the fluid actuation mechanism is adapted to reduce the effects of a physical wear of the parts of the sensing instrument over a number of test measurements.
 12. The method of claim 2 wherein the compensation of the fluid actuation mechanism is adapted to reduce the effects of the differences between individual fluid test samples over a number of test measurements.
 13. The method of claim 1 wherein the test measurement for each test sample is conducted in a prespecified constant time.
 14. A system for sensing at least one component concentration in a fluid test sample, comprising a reading apparatus and a disposable sensing device, the disposable sensing device comprising:at least one sensor; sample retaining means for retaining the fluid sample out of contact with the sensor prior to sensing; a sample conduit connecting the sample retaining means with the sensor; and sample displacement means for automatically and forcibly displacing the sample through the sample conduit and into contact with the sensor to enable sensing; the reading apparatus comprising: receiving means for receiving the disposable sensing device; control means for controlling the automatic displacement of the fluid test sample by the sample displacement means of the disposable sensing device; first memory means to store output characteristics of the sensor; and automatic compensation means for maintaining close to a target value the mean fluid displacement by adjusting input parameters of the control means in response to the stored output characteristics following each measurement.
 15. The system of claim 14 wherein the reading apparatus further comprises a second memory means to store preset values and means for comparing values stored in the first memory means and the second memory means to determine input parameters of the compensation means.
 16. The system of claim 15 wherein the reading apparatus further comprises means for displaying the results of the sensing and for providing an indication to the user whenever the output characteristics of the sensor are outside specified limits stored in the second memory means.
 17. The system of claim 14 wherein said target value of the mean fluid displacement is dynamically adjustable.
 18. An automatic compensation method for maintaining close to a target value the mean fluid displacement samples in a succession of test measurements of a fluid sensing instrument which includes an actuation mechanism for the displacement of fluids along a predetermined fluid path during each test measurement and at least one sensor, the method comprising the steps of:(a) storing in memory means a parameter associated with the target value of test fluid volume required to pass over the sensor; (b) recording the time of arrival of the test fluids at the sensor by measuring an output characteristic of the sensor; (c) following the recorded time of arrival, for each test fluid sample comparing an output characteristic of the sensor to the stored parameter value; and (d) compensating in response to the comparison the motion of the fluid actuation mechanism to keep the mean test sample fluid volume close to the target value.
 19. The method of claim 18 wherein the parameter associated with the target value of test fluid volume is the time required for the test sample to pass over the sensor for a constant speed of motion of the fluid actuation mechanism.
 20. The method of claim 18 wherein the parameter associated with the target value of test fluid volume is the speed of motion of the actuation mechanism for a constant test measurement time. 